B lymphocyte stimulator (BLyS) is a tumor necrosis factor (TNF) family member critical for maintenance of normal B cell development and homeostasis. It has been described by multiple names including BLyS (Moore et al. Science 1999; 285:260-263); BAFF (Schneider et al. J Exp Med 1999; 189:1747-1756); THANK (Mukhopadhyay et al. J Biol Chem 1999; 274:15978-15981); and TALL-1 (Shu et al. J Leukoc Biol 1999; 65:680-683). This ligand binds to three receptors in the TNF family: transmembrane activator and CAML interactor (TACI), B cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) (Gross et al. Nature 2000; 404:995-999 and Thompson et al. Science 2001; 293:2012-2013). In normal animals, BLyS is expressed by monocytes, macrophages, dendritic cells, neutrophils, and radiation-resistant (non-myeloid) cells hypothesized to be stromal cells of lymphoid organs (reviewed in Schneider, Curr Op Immunol 2005; 17:282-289). BLyS production has been shown to be regulated by various cytokines including interferon gamma (IFN-γ), granulocyte and macrophage colony stimulating factor (GM-CSF) and interleukin 10 (IL-10) (Scapini et al. J Exp Med 2003; 297-302 and Nardelli et al. Blood 2001; 97: 198-204).
Because overexpression of BLyS in transgenic animals resulted in autoimmune-like symptoms, reminiscent of systemic lupus erythematosus (SLE) and Sjörgens Syndrome (see Gross et al., supra.), investigation into BLyS levels in the clinic initially focused on autoimmune diseases. Genetic analysis of patients with SLE and rheumatoid arthritis (RA) discovered certain polymorphisms in the gene structure, although none of the polymorphisms could be associated in a statistically significant way with susceptibility to either disease (Kawasaki et al. Gen & Immun 2002; 3:424-429). However, one mutation (C→T at position −871) was shown to be associated with increased anti-Sm antibody and elevated monocyte BLyS levels.
Later work has focused on the role of BLyS in hematological malignancies. BLyS has been shown to be expressed in malignant B cells such as B chronic lymphocytic leukemia (B-CLL) cells Novak et al. Blood 2002; 100: 2973-2979), multiple myeloma (MM) (Novak et al. Blood 2004; 103:689-694), B-cell lymphoma (He et al. J Immunol 2004; 172: 3268-3279), and non-Hodgkin's lymphoma (NHL) (Briones et al. Exp Hematol 2002; 30:135-141). For NHL, levels of BLyS and its receptors has been correlated with disease activity and patient outcome (Novak et al. Blood 2004; 104: 2247-2253). Recently, overexpression of this ligand has been demonstrated in patients with Waldenstrom's Macroglobulinema (WM), a further B cell malignancy (Elsawa et al., manuscript in preparation).
An additional area where BLys levels have been measured is in T cells, particularly in association with T cell related diseases, including T cell malignancies and autoimmune diseases with strong T cell association such as multiple sclerosis (Krumbholz et al. 2005; J Exp Med 201:195) and rheumatoid arthritis (Matsumoto et al. Science 1999; 286: 1732-1753). Several groups have examined the significant effect of BLyS on T cell stimulation (Ng et al. J Immunol 2004; 173: 807 and Huard et al. Int Immunity 2004; 16: 467). A recent paper has broadened this observation to include Th1 and Th2 responses and T cell mediated inflammatory reactions (Sutherland et al. J Immunol 2005; 174: 5537-5544). Thus, it appears that BLyS may play a general role in hematological cancers whether originating from B cells or T cells.
There remains a need in the art for further identification of genetic polymorphisms of the BLyS gene or the sequences that control its expression that are statistically associated with hematological malignancies, such as B-cell malignancies. Such information is important for identifying individuals who have a propensity toward developing such hematological malignancies and for identifying new therapeutic agents for the treatment of these diseases. The present invention addresses this need by providing a polymorphism associated with both high BLyS levels and hematological cancers, and diagnostic tests determining the presence of this polymorphism.